Cervical Cancer

Diagnosis

Indications for Testing

  • Abnormal Pap smear; abnormal vaginal bleeding or discharge

Histology

  • Colposcopy and/or cervical biopsy necessary for definitive diagnosis
    • Should be considered for all grades of dysplasia on Pap smear
    • Refer to ASCCP guidelines  on suggested management of atypical squamous cells of undetermined significance (ASC-US), low-grade squamous intraepithelial lesion (LSIL), atypical squamous cells; cannot exclude high grade lesion (ASC-H), high-grade squamous intraepithelial lesion (HSIL) and atypical glandular cells (AGC)

Differential Diagnosis

Screening

  • Screening guidelines for cervical cancer

    Screening Guidelines for Cervical Cancer

    Guideline source:

    American Cancer Society (Oct 2010)

    American College of Obstetricians and Gynecologists (Aug 2003)

    U.S. Preventive Services Task Force (May 2011)

    National Comprehensive Cancer Network (Dec 2010)

    When to initiate screening

    Approximately 3 years after onset of vaginal intercourse or age 21, whichever comes first

    		Screening at 21 years

    Screening at 21 years; counseling and testing for sexually transmitted infections for patients <21 years

    Recommended screening intervals

    Conventional Pap

    Annually; every 2-3 years for women ≥30 with 3 negative cytology tests

    		Annually; every 2-3 years for women ≥30 with 3 negative cytology tests

    At least every 3 years

    Every 2 years for women 21-29 years; every 3 years for women ≥30 years with negative cytology and HPV testing

    Liquid-based cytology

    Every 2 years; every 2-3 years for women ≥30 with 3 negative cytology tests

    		Annually; every 2-3 years for women ≥30 with 3 negative cytology tests

    Same as conventional Pap

    If HPV testing used

    Every 3 years if HPV negative, cytology negative

    		Every 3 years if HPV negative, cytology negative

    Same as conventional Pap, including women previously immunized against HPV-16 and HPV-18

    When to discontinue screening

    Women ≥70 years of age with ≥3 recent, consecutive negative cytology tests, and no abnormal tests in the past 10 years

    		Women ≥65 years of age with negative cytology tests, who are not in a high-risk category for cervical cancer

    Women ≥65 years of age with ≥3 consecutive negative cytology tests and no abnormal test within the past 10 years

    Women who are status post total hysterectomy

    May discontinue testing if hysterectomy was for benign reasons and there is no history of high-grade dysplasia (CIN)

    May discontinue testing if hysterectomy was for benign reasons and there is no history of high-grade dysplasia (CIN)

    		May discontinue if hysterectomy was performed for benign indications

    Discontinue testing if hysterectomy was for benign reasons and no prior history of high-grade dysplasia (CIN)

  • Cervicovaginal cytology (Pap test) is used for screening, particularly for detecting early pre-cancerous lesions
  • HPV genotyping recommended for women >30 years with negative cytology and positive HPV test

Monitoring

  • Biomarker – SCCA (squamous cell carcinoma antigen)
    • Potentially useful marker of recurrence
  • Pap smear – not sensitive enough for monitoring

Clinical Background

Carcinoma of the cervix was once the most common cause of cancer in women.

Epidemiology

  • Prevalence – estimated 12,200 new cases in the U.S. in 2010
    • Third most common cancer in women worldwide
  • Age – median is 48 years; infection with oncogenic strain of human papillomavirus (HPV) associated with earlier age of onset
    • High-grade dysplasia in 30s
    • Invasive carcinoma in 40s

Risk Factors

  • Sexual activity
    • Infection with oncogenic (high-risk) types of HPV 
      • 15% of U.S. women 14-59 years test positive for a high-risk strain of  HPV
    • History of early sexual activity, especially with multiple sex partners
    • Sexual partner who began sexual activity at an early age or who had many previous sexual partners
    • History of sexually transmitted infections (STIs)
  • Family history of cervical cancer
  • Previous diagnosis of dysplasia on a Pap test or prior gynecological malignancy
  • Tobacco use
  • Exposure to diethylstilbestrol (DES) before birth
  • HIV infection
  • Weakened immune system (eg, organ transplant, chemotherapy, chronic corticosteroid use)

Pathophysiology

  • Etiology – HPV, particularly the oncogenic types
    • HPV 16 and 18 are responsible for >70% of invasive cervical cancers
  • Tumor types – 80% are squamous cell carcinoma, 20% are adenocarcinomas
    • Increased incidence of adenocarcinomas over last 30 years
      • Cytologic screening methods are less effective for adenocarcinomas, but HPV testing may improve detection rates
  • Usually evolves from cervical dysplasia
    • 30-35% of high-grade dysplasias progress to invasive carcinoma

Clinical Presentation

  • Earliest stage may be asymptomatic or have a watery vaginal discharge
  • Abnormal vaginal bleeding or a significant unexplained change in menstrual cycle
  • A friable cervix that bleeds easily following intercourse or contact (eg, insertion of a diaphragm, collection of a Pap smear)
  • Pain during sexual intercourse
  • Abnormal vaginal discharge containing blood-tinged mucous

Treatment

Prevention

  • FDA-approved recombinant vaccine (Gardasil®) is effective against HPV types 6, 11, 16 and 18 and is approved for use in males and females 9-26 years

Indications for Laboratory Testing

  • Tests generally appear in the order most useful for common clinical situations
  • Click on number for test-specific information in the ARUP Laboratory Test Directory
Test Name and Number Recommended Use Limitations Follow Up
Cytology, SurePath Liquid-Based Pap Test 2000134
Method: Microscopy

Replacement for conventional gynecologic Pap smears for use in the screening and detection of cervical cancer, precancerous lesions, atypical cells and all other cytologic categories as defined by the Bethesda System for Reporting Cervical/Vaginal Cytologic Diagnoses

For 5-year gap testing, HPV testing should be added

Although this screening test has a low probability of error, patient should be reminded to consult physician immediately if she experiences any suspicious signs or symptoms, regardless of her Pap test result

  
Cytology, SurePath Liquid-Based Pap Test with Reflex to Human Papillomavirus (HPV) DNA Probe, High Risk 2000135
Method: Microscopy/Nucleic Acid Probe

Replacement for conventional gynecologic Pap smears for use in the screening and detection of cervical cancer, precancerous lesions, atypical cells and all other cytologic categories as defined by the Bethesda System for Reporting Cervical/Vaginal Cytologic Diagnoses

Although this screening test has a low probability of error, patient should be reminded to consult physician immediately if she experiences any suspicious signs or symptoms, regardless of her Pap test result

Reflexes to HPV DNA probe only if Pap test results are abnormal; therefore, this test cannot be used for 5-year gap testing

  
Cytology, SurePath™ Liquid-Based Pap Test (AutoCyte PREP™ System) with Reflex to Human Papillomavirus (HPV) DNA Probe, High Risk 8100214
Method: Microscopy/Nucleic Acid Probe

Triage ASC-US cervical cytology

Follow up treated/untreated histologic CIN1

Follow up LSIL in adolescent females

When results are negative, no testing is recommended for 3 years because the negative predictive value of this test is very high

Results should be correlated with cytologic and histologic findings

False-negatives due to inadequate cellularity can occur

Cross-reactions with other genotypes (eg, low-risk) may occur

See 2006 Consensus Guidelines for the Management of Women with Cervical Cytologic Abnormalities in Guidelines section of topic
Cytology, ThinPrep® Pap Test 2000137
Method: ThinPrep® 2000 System/Routine Cytopathologic Evaluation

Replacement for conventional gynecologic Pap smears for use in the screening and detection of cervical cancer, precancerous lesions, atypical cells and all other cytologic categories as defined by the Bethesda System for Reporting Cervical/Vaginal Cytologic Diagnoses

Although this screening test has a low probability of error, patient should be reminded to consult physician immediately if she experiences any suspicious signs or symptoms, regardless of her Pap test result

  
Cytology, ThinPrep® Pap with Reflex to Human Papillomavirus (HPV) DNA Probe, High Risk 8100212
Method: ThinPrep® 2000 System/Microscopy/Nucleic Acid Probe

Initial screening for cervical pathology

When results are negative, no testing is recommended for 3 years because the negative predictive value of this test is very high

Results should be correlated with cytologic and histologic findings

False-negatives due to inadequate cellularity can occur

Cross-reactions with other genotypes (eg, low-risk) may occur

See 2006 Consensus Guidelines for the Management of Women with Cervical Cytologic Abnormalities in Guidelines section of topic
Human Papillomavirus (HPV) DNA Probe, High Risk, Cervical Brush (Digene) 0065999
Method: Qualitative Nucleic Acid Probe

Triage ASC-US cervical cytology in women ≥21 years

Primary screening in conjunction with cervical pap test in women ≥30 years

Follow up treated/untreated histologic CIN1

Follow up LSIL in adolescent females

Determine “test of cure” following treatment (LEEP, Cone) for histologic-proven cervical abnormalities (CIN2,3/Ca)

Detects high-risk HPV genotypes 16 and 18 only; cross reactivity with high levels of high-risk HPV genotype 31 has been observed and may return an HPV 16-positive result

 Results should be correlated with cytologic and histologic findings

Cross-reactions with other genotypes (eg, low-risk) may occur

False-negative results due to inadequate cellularity can occur

  
Human Papillomavirus (HPV) DNA Probe, High-Risk Surepath™  (AutoCyte) 0060744
Method: Qualitative Nucleic Acid Probe

Triage ASC-US cervical cytology in women ≥21 years

Primary screening in conjunction with cervical pap test in women ≥30 years

Follow up treated/untreated histologic CIN1

Follow up LSIL in adolescent females

Determine “test of cure” following treatment (LEEP, Cone) for histologic-proven cervical abnormalities (CIN2,3/Ca)

Detects high-risk genotypes 16, 18; 31, 33, 35, 39, 45, 51, 56, 58, 59, 68 (associated with cervical cancer and precursor lesions)

Results should be correlated with cytologic and histologic findings

Cross-reactions with other genotypes (eg, low-risk) may occur

False-negative results may occur due to inadequate cellularity or specimen instability due to transport in SurePath medium

  
Human Papillomavirus (HPV) DNA Probe, High Risk (ThinPrep®) 0060750
Method: Qualitative Nucleic Acid Probe

Triage ASC-US cervical cytology in women ≥21 years

Primary screening in conjunction with cervical pap test in women ≥30 years

Follow up treated/untreated histologic CIN1

Follow up LSIL in adolescent females

Determine “test of cure” following treatment (LEEP, Cone) for histologic-proven cervical abnormalities (CIN2,3/Ca)

Detects high-risk genotypes 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68 (associated with cervical cancer and precursor lesions)

Results should be correlated with cytologic and histologic findings

Cross-reactions with other genotypes (eg, low-risk) may occur

False-negative results due to inadequate cellularity can occur

  
Human Papillomavirus (HPV), High Risk, E6/E7 mRNA by Transcription-Mediated Amplification (TMA) with Reflex to Genotypes 16 and 18/45 2007890
Method: Qualitative Target Amplification Nucleic Acid Probe

Screen for cervical cancer in women ≥30 years

Detects E6/E7 viral messenger RNA of the high-risk HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68 associated with cervical cancer and its precursor lesions

If HPV high risk is positive, HPV genotypes 16, 18/45 testing is added

    
Squamous Cell Carcinoma Antigen, Serum 0081054
Method: Quantitative Enzyme-Linked Immunosorbent Assay

May be helpful in monitoring for recurrent disease

Results obtained with different assay methods or kits cannot be used interchangeably

SCC antigen levels alone should not be interpreted as evidence of the presence or absence of malignant disease

In patients with known or expected cancer, other tests and procedures must be considered for diagnosis and patient management
Additional Tests Available
 
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Cytology, Pap Smear 2000624
Method: Microscopy

Use for screening and detection of cervical cancer
Human Papillomavirus (HPV) High Risk in situ Hybridization, Paraffin 2002899
Method: In situ Hybridization

Detects high-risk genotypes16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 66 (associated with cervical cancer and precursor lesions)

Used to test FFPE tissue biopsy samples